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Biotechs Wage War on Superbugs

With antibiotic resistance on the rise, three biotechs are developing new ways to wage war on superbugs.

Multidrug-resistant infections are the new plague. The most publicized, methicillin-resistant Staphylococcus aureus (or MRSA), causes nearly 19,000 deaths in the United States each year — more than AIDS. Today, 70% of infections are impervious to at least one antibiotic, prompting many clinicians to prescribe multiple drugs. And new antibiotics aren't the answer: Bacteria often begin to show resistance during clinical trials, before doctors have even had a chance to administer the drugs. The Achilles' heel of antibiotics? They poison most bacteria, but allow the hardiest to survive and breed drug-resistant progeny.

Our best hope of defeating antibiotic resistance, says Georgetown University immunologist Michael Zasloff, is to develop drugs that kill bacteria so immediately and thoroughly that they can't evolve resistance. "A drug like penicillin targets an enzyme, and it's easy for an organism to develop a single mutation to get past that," he says. "But when a drug destroys a bacterium's entire membrane, it's very difficult for the bacterium to redesign it." Here, three biotechs that have adopted a scorched-earth approach.

Illustration by Headcase Design


Eastern European doctors have long recognized the power of phages — naturally occurring bacteria-eating viruses — to treat antibiotic-resistant infections. The United States hasn't quite caught on yet, but Intralytix, a Baltimore company that manufactures phage-based products to kill bacteria on food, is looking to change that. "We're concentrating on fighting multidrug-resistant bacteria and on building a drug that's effective against MRSA," says CEO John Vazzana. "Enormous amounts of data show phages really do work."

Phages destroy bacteria from the inside out. They enter a bacterium through its membrane (I) and deposit DNA inside, where the phages replicate (II). Baby phages burst out of the bacterium, exploding it like a water balloon (III), and head after other bacteria. Intralytix recently concluded a Phase I human trial at a Texas wound-care clinic, which showed that phage therapy is safe, and is seeking funding for a Phase II trial to demonstrate efficacy against infections like MRSA.

One potential sticking point: the Food and Drug Administration. Since each species of phage attacks one specific type of bacteria, phages work best in a cocktail custom-mixed to combat the particular bacteria causing a patient's infection. FDA policy calls for trials of each combination of phages. But FDA guidelines have accommodated flu vaccines, which must be changed several times a year to keep up with the evolving virus. "I'm an eternal optimist," Vazzana says. "I think that within five years, the FDA will approve a phage-based drug."

Illustration by Headcase Design


"When you put mild environmental pressure on billions of bacteria," says Ron Najafi, the CEO of Emeryville, California — based NovaBay, "there's enough genetic diversity that you can kill them all except one, and that one becomes the predominant player." Casting about for a more effective weapon, NovaBay scientists decided to take a cue from the body's own immune system. The result is an experimental drug, dubbed an aganocide, which is patterned after small molecules that white blood cells churn out to defend the body against invading pathogens. These molecules bind to the membrane of the bacterial cell (I) and deliver a payload of toxic chloronium ions that envelop it. This chlorine cover causes irreversible damage to a vast range of proteins on the cell's surface, rendering the bacteria noninfectious (II). "Antibiotics might attack one enzyme," Najafi says, "but we attack billions and billions."

NovaBay recently inked a $10 million deal with eye-care provider Alcon to give the company access to its drug technology. Human clinical trials evaluating aganocides' effectiveness in treating eye infections began in January, and a trial on ear-infection patients will begin later this year. Najafi also has big plans to use his creations against bugs outside the bacterial universe: "These compounds are extremely antibacterial, antifungal, and antiviral. The critical thing we're doing is attacking the problem using the body's own mechanism of action, which we already know has been successful."

Illustration by Headcase Design


Like NovaBay, Radnor, Pennsylvania — based PolyMedix looks to the body's immune system for inspiration — in its case, a particular class of naturally occurring human-host defense proteins called "defensins." These proteins entrench themselves in a bacterium's membrane, creating small pores and defects. As a result, essential ions and nutrients flow out, and the pathogen dies without reproducing. "It's a direct attack, like a needle punching a hole in a balloon," says CEO Nick Landekic. "You're literally killing the bacterium mechanically."

Because the defensins overwhelm bacteria's external defenses all at once, the bacteria have few chances to regroup and emerge leaner and meaner, as they typically do in response to antibiotics. "Many of the big pharma companies have tried to use animal-host defense proteins in drugs, but it didn't work," Landekic says. "We've succeeded because we have a computer-aided drug-design approach that helps us study how these natural proteins work and create artificial drug molecules."

In PolyMedix's Phase I safety trial of its anti-Staphylococcus aureus compound, concluded this past December, no subjects suffered severe side effects, even when they had concentrations of the drug in their blood sufficient to kill staph bacteria. A Phase II efficacy trial may begin by the end of 2009. Landekic is already investigating ways to fast-track the drug's FDA approval. "This is a huge market opportunity," he says. "Staph is such a major problem that the alternative to treatment is often death."

A version of this article appeared in the May 2009 issue of Fast Company magazine.

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